Therapeutic agent for senile dementia

ABSTRACT

A therapeutic/preventive agent for cognitive dysfunctions, which comprises as an active ingredient an imide derivative of the following formula [1]: 
     
       
         
         
             
             
         
       
     
     wherein Z is a group of the formula [2]: 
     
       
         
         
             
             
         
       
     
     D is a group of —(CH 2 ) p -A-(CH 2 ) q —; G is ═N—, —CH—, etc.; and Ar is an aromatic heterocyclic group, etc.

This application is a Divisional of co-pending application Ser. No.10/562,039 filed on Dec. 22, 2005, which is a national phase applicationof International Application No. PCT/JP2004/009095 filed on Jun. 22,2004, which claims priority to JP 2003/178386 filed in Japan on Jun. 23,2003 under 35 U.S.C. §119; the entire contents of all are herebyincorporated by reference.

TECHNICAL FIELD

The present invention relates to a therapeutic agent for dementia, moreparticularly, a therapeutic agent for dementia, which comprises as anactive ingredient an imide derivative.

BACKGROUND ART

Senile dementia is divided broadly into the Alzheimer type dementia andthe cerebrovascular dementia, and about 80% of the patients of seniledementia can be classified into these categories. As the populationrapidly ages, the number of the patients of senile dementia demonstratesan upward trend in these days. In Japan, it is speculated that about 7%of the people 65 years old or over show the symptoms of dementia, andhence, it is an urgent need to develop an excellent therapeutic agentfor dementia. The Alzheimer type dementia is accompanied by senileplaque and neurofibrillary tangle, and it is pathologicallycharacterized by encephalatrophy caused by significant neuronal death.In familial Alzheimer's disease, several gene mutations have beenidentified, whereby a leading hypothesis for neuronal pathogeneticmechanism thereof has been speculated, but the most of cases aresporadic, and hence, it may be said that Alzheimer's disease is still adisease of unknown cause. Accordingly, at the present, there is noradical therapeutic method for inhibiting neurodegeneration. TheAlzheimer type dementia shows as core symptoms cognition dysfunctionssuch as disorders of memory, faculty of orientation, attention, etc.,and it is also accompanied by peripheral symptoms such as psychoticmanifestations or abnormal behavior problems (e.g., depression,aggressive attack, delusion, etc.). In the symptomatic treatment ofthese symptoms, only an acetylcholine esterase inhibitor has beenclinically used, and it has been reported that acetylcholine esteraseinhibitors are also effective to not only core symptoms but alsoperipheral symptoms. In the treatment with acetylcholine esteraseinhibitors, neurotransmitter acetylcholine is supplemented by inhibitingacetylcholine-degrading enzyme, while acetylcholine neuronal cells,which are closely-linked with cognitive function, are especiallydisturbed in Alzheimer's disease and neurotransmitter acetylcholine isreduced.

On the other hand, the cerebrovascular dementia is a disease whichdevelops owing to cerebrovascular disorders, and at the moment, there isno cure for core symptoms thereof. However, recently, the clinical trialof acetylcholine esterase inhibitors has been done, and it has becomeapparent that these medicaments are also effective to cerebrovasculardementia. Accordingly, there is a possibility that a therapeutic agenthaving a similar therapeutic mechanism to the Alzheimer's disease suchas acetylcholine esterase inhibitors may be effective even tocerebrovascular dementia (e.g., Rinsho-Seishinigaku (i.e., ClinicalPsychiatry), 31 (10): 1189-1193 (2002)).

On the other hand, there has not been known any therapeutic agent whichshows no acetylcholine esterase inhibitory activity but is effective tosenile dementia such as the Alzheimer type dementia and thecerebrovascular dementia. Moreover, JP Patent No. 2800953 disclosesimide derivatives showing an excellent antipsychotic activity andanxiety reducing activity, but it has never indicated whether or notthose derivatives show effects on senile dementia.

DISCLOSURE OF INVENTION

The present invention provides a therapeutic agent for senile dementia.More particularly, the present invention provides a therapeutic agenteffective to both of the core symptoms and the peripheral symptoms ofsenile dementia.

The present inventors have intensively studied in order to solve theabove problems, and found that the imide compound of the presentinvention exhibits a therapeutic effect in cognitive/memory disturbancemodels produced by acetylcholine receptor blocker, which arerepresentative animal models for senile dementia, and finally they haveaccomplished the present invention.

Namely, the present invention relates to the following:

(1) A therapeutic/preventive agent for cognitive dysfunctions, whichcomprises as an active ingredient an imide derivative of the formula[1]:

(wherein Z is a group of the formula [2]:

(in which B is a carbonyl or a sulfonyl; R¹R², R³ and R⁴ areindependently a hydrogen atom or a lower alkyl, provided that R¹ and R²,or R¹ and R³ may combine each other to form a hydrocarbon ring, or R¹and R³ may combine each other to form an aromatic hydrocarbon ring; saidhydrocarbon ring may optionally be cross-linked with a lower alkylene oran oxygen atom; said lower alkylene and hydrocarbon ring may optionallybe substituted by at least one alkyl; and n is 0 or 1),D is a group of the formula [3]:

—(CH₂)_(p)-A-(CH₂)_(q)—  [3]

(in which A is a hydrocarbon ring optionally be cross-linked with alower alkylene or an oxygen atom; said lower alkylene and hydrocarbonring may optionally be substituted by at least one alkyl; and p and qare independently 0, 1 or 2),G is N, CH or COH, and —Ar is an aromatic heterocyclic group, anaromatic hydrocarbon group, benzoyl, phenoxy, or phenylthio, orG is a carbon atom, and —Ar is biphenylmethylidene,where said aromatic heterocyclic group, aromatic hydrocarbon group,benzoyl, phenoxy or phenylthio, and biphenylmethylidene may optionallybe substituted by at least one group selected from a lower alkyl, alower alkoxy and a halogen atom},or an acid addition salt thereof.(2) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (1), which is a therapeutic agent for seniledementia.(3) A therapeutic/preventive agent for cognitive dysfunctions, whichcomprises as an active ingredient an imide derivative of the aboveformula [1], wherein —Ar is an aromatic heterobicyclic group, naphthyl,benzoyl, phenoxy or phenylthio and G is N, CH or COH, or —Ar isbiphenyl-methylidene and G is a carbon atom (said aromaticheterobicyclic group, naphthyl, benzoyl, phenoxy, phenylthio andbiphenylmethylidene may optionally be substituted by at least one groupselected from a lower alkyl, a lower alkoxy and a halogen atom), or anacid addition salt thereof.(4) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (3), which is a therapeutic agent for seniledementia.(5) A therapeutic/preventive agent for cognitive dysfunctions, whichcomprises as an active ingredient an imide derivative of the aboveformula [1], wherein —Ar is an aromatic heterocyclic group condensedwith a benzene ring, or naphthyl, benzoyl, phenoxy or phenylthio (saidaromatic heterocyclic group condensed with a benzene ring, naphthyl,benzoyl, phenoxy, and phenylthio may optionally be substituted by atleast one group selected from a lower alkyl, a lower alkoxy and ahalogen atom), and G is N, CH or COH, or an acid addition salt thereof.(6) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (5), which is a therapeutic agent for seniledementia.(7) A therapeutic/preventive agent for cognitive dysfunctions, whichcomprises as an active ingredient an imide derivative of the aboveformula [1], wherein Z is a group of the formula [4]:

in which -L- is a single bond or a double bond, E is a lower alkyleneoptionally substituted by a lower alkyl, or an oxygen atom, R⁵ is ahydrogen atom or a lower alkyl, and B is the same as defined in theabove (1);a group of the formula [5]:

in which -L-, E, R⁵ and B are as defined above;a group of the formula [6]:

in which R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ are independentlya hydrogen atom or a lower alkyl, or the adjacent two groups of R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ may combine each other to form adouble bond, and B is as defined above;a group of the formula [7]:

in which R¹⁶ and R¹⁷ are independently a hydrogen atom or a lower alkyl,or R¹⁶ and R¹⁷ may combine each other to form a saturated hydrocarbonring, and R⁵ and B are as defined above; ora group of the formula [8]:

in which B is as defined above,or an acid addition salt thereof.(8) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (7), which is a therapeutic agent for seniledementia.(9) A therapeutic/preventive agent for cognitive dysfunctions, whichcomprises as an active ingredient an imide derivative of the formula[9]:

or an acid addition salt thereof.(10) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (9), which is a therapeutic agent for seniledementia.(11) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (2), (4), (6), (8) or (10), which is atherapeutic agent for the Alzheimer type dementia.(12) The therapeutic/preventive agent for cognitive dysfunctionsaccording to the above (2), (4), (6), (8) or (10), which is atherapeutic agent for the cerebrovascular dementia.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows the effects of the imide derivative on rats in onestep-through passive avoidance test where the acetylcholine receptorblocker scopolamine was used for inducing amnesia, and indicates thestep-through latency during the training (*: P<0.05 vs the group treatedwith 0.5% MC+scopolamine (Steel's test)).

FIG. 2 shows the effects of the imide derivatives on rats in onestep-through passive avoidance test where the acetylcholine receptorblocker scopolamine was used for inducing amnesia, and indicates thestep-through latency during the test (*: P<0.05 vs the group treatedwith 0.5% MC+scopolamine (Steel's test), #: •<0.01 vs the group treatedwith 0.5% MC+saline solution (Mann-Whitney test)).

BEST MODE FOR CARRYING OUT THE INVENTION

Each group of the imide derivative of the formula [1] of the presentinvention are explained in detail.

The lower alkylene for Z and A includes, for example, ones having notmore than 3 carbon atoms such as methylene, ethylene, trimethylene, etc.

The hydrocarbon ring for Z and A includes, for example, a cycloalkane orcycloalkene having not more than 7 carbon atoms. The cycloalkane havingnot more than 7 carbon atoms includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc. Thecycloalkene having not more than 7 carbon atoms includes, for example,cyclopentene, cyclohexene, cycloheptene, etc.

The hydrocarbon ring being cross-linked with a lower alkylene or anoxygen atom for Z and A includes, for example, rings having not morethan 10 carbon atoms such as bicyclo[1.1.1]pentane,bicyclo[2.1.1]hexane, bicyclo[2.1.1]hex-2-ene, bicyclo[2.2.1]heptane,bicyclo[2.2.1]hept-2-ene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene,bicyclo[4.1.1]octane, bicyclo-[4.1.1]oct-2-ene, bicyclo[4.1.1]oct-3-ene,bicyclo[3.2.1]octane, bicyclo-[3.2.1]oct-2-ene, bicyclo[3.2.1]oct-3-ene,bicyclo[3.2.1]oct-6-ene, bicyclo-[3.2.2]nonane, bicyclo[3.2.2]non-2-ene,bicyclo[3.2.2]non-3-ene, bicyclo-[3.2.2]non-6-ene,2-oxabicyclo[1.1.1]butane, 2-oxabicyclo[2.1.1]pentane,2-oxabicyclo[2.1.1]pent-4-ene, 7-oxabicyclo[2.2.1]hexane,7-oxabicyclo-[2.2.1]hex-2-ene, 7-oxabicyclo[4.1.1]heptane,7-oxabicyclo[4.1.1]hept-2-ene, 7-oxabicyclo[4.1.1]hept-3-ene,8-oxabicyclo[3.2.1]heptane, 8-oxabicyclo[3.2.1]hept-2-ene,8-oxabicyclo[3.2.1]hept-3-ene, 8-oxabicyclo-[3.2.1]hept-6-ene, etc.

The aromatic hydrocarbon ring for Z includes, for example, ones havingnot more than 10 carbon atoms such as phenyl ring, naphthyl ring, etc.

The binding position of the hydrocarbon ring for A includes, forexample, -1, 1-, -1,2-, -1,3-, -1,4-, etc.

The aromatic hydrocarbon group for —Ar includes, for example, oneshaving not more than 10 carbon atoms such as phenyl, naphthyl, etc. Thearomatic heterocyclic group for —Ar includes, for example, an aromaticheteromonocyclic group and an aromatic heterobicyclic group.

The aromatic heteromonocyclic group includes, for example, ones havingnot more than 6 carbon atoms, and further having the same or different 1to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and asulfur atom, such as pyridyl, pyrimidinyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, furyl, imidazolyl, etc.

The aromatic heterobicyclic group includes, for example, ones having notmore than 10 carbon atoms, and further having the same or different 1 to5 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfuratom, such as benzolog-fused rings (e.g., benziso-thiazolyl,benzisoxazolyl, benzofuryl, quinolyl, isoquinolyl, indolyl, indazolyl,benzimidazolyl, benzoxazolyl, etc.), naphthyridinyl, puteridinyl,thienofuranyl, imidazothiophen-yl, imidazofuranyl, etc.

The alkyl includes, for example, ones having not more than 6 carbonatoms, and preferably lower alkyl groups having not more than 4 carbonatoms, such as methyl, ethyl, propyl, 2-propyl, butyl, etc. The loweralkyl includes, for example, ones having not more than 4 carbon atoms,such as methyl, ethyl, propyl, 2-propyl, butyl, etc.

The lower alkoxy includes, for example, ones having not more than 4carbon atoms, such as methoxy, ethoxy, propoxy, 2-propoxy, butoxy, etc.

The halogen atom is fluorine, chlorine, bromine, iodine.

The present compound [1] may have stereoisomers and/or an opticalisomer. The present invention also includes a mixture of these isomersor each isolated isomer.

The preferable group for —Ar is an aromatic heterobicyclic group, ornaphthyl, benzoyl, phenoxy or phenylthio (in these cases, G is N, CH, orCOH), or biphenylmethylidene (in this case, G is a carbon atom), wheresaid aromatic heterobicyclic group, naphthyl, benzoyl, phenoxy,phenylthio and biphenylmethylidene may optionally be substituted by atleast one group selected from a lower alkyl, a lower alkoxy and ahalogen atom.

The more preferable group for —Ar is a benzolog-fused ring, naphthyl,benzoyl, phenoxy, or phenyl (said benzolog-fused ring, naphthyl,benzoyl, phenoxy, and phenylthio may optionally be substituted by atleast one group selected from a lower alkyl, a lower alkoxy and ahalogen atom), and in this case, G is N, CH or COH.

The further preferable group for —Ar is benzisothiazolyl,benzisoxazolyl, isoquinolyl, benzofuranyl, indazolyl or indolyl (saidbenzisothiazolyl, benzisoxazolyl, isoquinolyl, benzofuranyl, indazolyland indolyl may optionally be substituted by at least one group selectedfrom a lower alkyl, a lower alkoxy and a halogen atom), and in thiscase, G is N, CH or COH.

The preferable group for Z is, for example, a group of the formula [4]:

(in which -L- is a single bond or a double bond, E is a lower alkyleneoptionally substituted by a lower alkyl, or an oxygen atom, R⁵ is ahydrogen atom or a lower alkyl, and B is a carbonyl or a sulfonyl);a group of the formula [5];

(in which -L-, E, R⁵ and B are as defined above);a group of the formula [6]:

(in which R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ are independentlya hydrogen atom or a lower alkyl, or the adjacent two groups of R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ may combine each other to form adouble bond, and B is as defined above);a group of the formula [7]:

(in which R¹⁶, R¹⁷ are independently a hydrogen atom or a lower alkyl,or R¹⁶ and R¹⁷ may combine each other to form a saturated hydrocarbonring, and R⁵ and B are as defined above); ora group of the formula [8]:

(in which B is as defined above), etc.

Then, the saturated hydrocarbon ring formed by combining R¹⁶ and R¹⁷includes, for example, a cycloalkane having not more than 7 carbonatoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, etc.

The preferable group for Z is, for example, a group of the formula [10]:

(in which -L′- is a single bond, E is a lower alkylene optionallysubstituted by a lower alkyl, or an oxygen atom, R⁵ is a hydrogen atomor a lower alkyl, and B is a carbonyl or a sulfonyl);a group of the formula [11]:

(in which -L′-, E, R⁵ and B are as defined above);a group of the formula [12]:

(in which R^(6′), R^(7′), R^(8′), R^(9′), R^(10′), R^(11′), R^(12′),R^(13′), R^(14′), R^(15′) are independently a hydrogen atom or a loweralkyl, and B is as defined above);a group of the formula [7]:

(in which R¹⁶, R¹⁷, R⁵ and B are as defined above); ora group of the formula [8]:

(B is as defined above).

The imide derivative of the present invention or an acid addition saltthereof may be prepared, for example, by the method disclosed in JPPatent No. 2800953 1 as mentioned above.

The imide derivative of the present invention may be used in the form ofa pharmaceutically acceptable acid addition salt thereof. Inorganicacids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.or organic acids such as fumaric acid, citric acid, tartaric acid,succinic acid, etc. may be exemplified as an acid for forming additionsalts.

The imide derivative or a pharmaceutically acceptable acid addition saltthereof, which is the active compound of the present invention, may beadministered at a dose suitable for necessity of each case in aconventional dosage form. For example, it can be administered orally inthe form of tablets, capsules, syrups, suspension, etc. or parenterallyin the form of injection preparation such as liquid preparations (e.g.,solutions, emulsions, suspension, patches, etc.).

In addition, the above-mentioned suitable dosage forms may be preparedby mixing an active compound with a conventional pharmaceuticallyacceptable carriers, excipients, binders, stabilizers, etc. When used inthe form of injection, it may additionally contain buffering agents,solublizers, isotonic agents, etc.

The dose and the frequency of the administration of the presenttherapeutic agent may vary according to the dosage forms, or theseverity of the diseases to be treated. For example, the imidederivative is orally administered at a dose of 1 to 200 mg per day in anadult, which is administered once a day or divided into several dosageunits.

The diseases to which the therapeutic agent of the present invention iseffective are the Alzheimer type and the cerebrovascular dementia, moreparticularly, various senile dementias (e.g., dementia with Lewy bodies,dementia from Pick's disease, dementia from Creutzfeldt-Jakob disease,dementia from Huntington's chorea, dementia from Parkinson's disease,etc.) including multiple infarct dementia, dementia caused by cerebralinfarction, Binswanger disease, dementia caused by stroke, amyloidangiopathy, ischemic dementia. Further, the therapeutic agent of thepresent invention shows the improving activity of cognitive dysfunctionsaccompanied by acetylcholine neuronal dysfunctions, and hence, it may beused in the treatment of traumatic cognitive dysfunctions, dementia inDown syndrome, schizophrenial cognitive dysfunctions, or cognitivedysfunctions accompanied by acetylcholine neuronal dysfunctions from anycause, in addition to the treatment of senile dementia.

EXAMPLES

The present invention is illustrated in more detail by Examples, but thepresent invention should not be construed to be limited thereto.

Example 1 Method

Male Wistar rats (7 weeks old) were used. As a test medicament,(1R,2S,3R,4S)—N-|(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl-methyl]-1-cyclohexylmethyl]-2,3-bicycl[2.2.1]heptanedicarboxylmide(Compound A) was suspended in 0.5% methyl cellulose (MC) solution. As anagent for inducing amnesia, scopolamine (manufactured by Wako PureChemical Industries, Ltd., product No. 198-07901), which is anacethylcoline receptor blocker, was dissolved in saline solution(manufactured by TERUMO CORPORATION). Compound A at a dose of 3 mg/kg or30 mg/kg, or 0.5% MC as a control was orally administered to the animalsone hour prior to the training step in the one step-through passiveavoidance test, and then, scopolamine at a dose of 0.5 mg/kg or a salinesolution as a control was subcutaneously administered to the animals 30minutes prior to the training step. The volume of each solution to beadministered was 5 ml/kg each.

The one step-through passive avoidance test in rats was carried out inthe following manners with using an apparatus consisting of a light-darkbox and an electric stimulator (manufactured by O'hara & Co., Ltd.,product no. PA-2030A) as an experimental apparatus. Namely, on Day 1,after the medicament and the agent for inducing amnesia wereadministered, the rats were put into the light box of the experimentalapparatus where the back of each rat was directed to the dark box. Then,10 seconds later, a guillotine door set at the border between the darkbox and the light box was opened. Due to the habits of the rats, oncethe rats entered into the dark box, the guillotine door was quicklyclosed. At three seconds after the entering into the dark box, anelectroconvulsive shock (0.5 mA, for 3 seconds) was given to the rats.Again, the guillotine door was opened, and after the rats spontaneouslyreturned to the light box, the animals were transferred into the homecage. The period between the time just after the guillotine door wasopened and the time at which the rats entered into the dark box wasmeasured as a step-through latency. As to the animals which did notenter into the dark room even after 300 seconds, the training wasterminated, and those animals were dropped in the following experimentfor the reasons of training failure.

On Day 2 of the experiment, a test was carried out about 24 hours afterthe training. The procedures of the test were carried out in the samemanner to the training step except that an electroconvulsive shock wasnot given. The step-through latency in the test was measured up to 300seconds, and the step-through latency over 300 seconds was regarded as300 seconds. FIG. 1 and FIG. 2 show the effects of Compound A on thescopolamine-induced cognitive/memory dysfunction models in the onestep-through passive avoidance test when it was orally administered at adosage of 3 mg/kg or 30 mg/kg. FIG. 1 shows the step-through latencyduring the training step, and FIG. 2 shows the step-through latencyduring the test. The number of the animals was 15 per group, and thedata was expressed in mean±SEM.

(Results)

The agent for inducing amnesia, scopolamine did not affect on thestep-through latency during the training. Compound A slightly shortenedthe step-through latency during the training step at a dose of 3 mg/kg.During the test, the animals treated with scopolamine showed asignificantly shorter step-through latency as compared to the animalstreated with saline solution (cognitive/memory dysfunction inducingeffect). In the group treated with both of Compound A at a dose of 30mg/kg and scopolamine, the step-through latency was significantlyextended. That is, it was observed that Compound A exhibited animproving effect of scopolamine-induced cognitive/memory dysfunctions.Thus, it was found that the imide derivatives may exhibit an improvingactivity of scopolamine-induced cognitive/memory dysfunctions, and as aresult, it may become apparent that the present invention may provide atherapeutic method for senile dementia and a therapeutic agent for saidmethod.

INDUSTRIAL APPLICABILITY

According to the present invention, it was found that the imidederivatives may exhibit an improving activity of scopolamine-inducedcognitive/memory dysfunctions, and as a result, it has become apparentthat the present invention may provide a therapeutic method for seniledementia and a therapeutic agent for said method.

1. A method for treatment of senile dementia, which comprisesadministering an effective amount of an imide derivative of the formula:

{wherein Z is a group of the formula:

(in which B is a carbonyl or a sulfonyl; R¹R², R³ and R⁴ areindependently a hydrogen atom or a lower alkyl, provided that R¹ and R²,or R¹ and R³ may combine each other to form a hydrocarbon ring, or R¹and R³ may combine each other to form an aromatic hydrocarbon ring; saidhydrocarbon ring may optionally be cross-linked with a lower alkylene oran oxygen atom; said lower alkylene and hydrocarbon ring may optionallybe substituted by at least one alkyl; and n is 0 or 1), D is a group ofthe formula:—(CH₂)_(p)-A-(CH₂)_(q)—  [3] (in which A is a hydrocarbon ringoptionally be cross-linked with a lower alkylene or an oxygen atom; saidlower alkylene or said hydrocarbon ring may optionally be substituted byat least one alkyl; and p and q are independently 0, 1 or 2), G is N, CHor COH, and —Ar is an aromatic heterocyclic group, an aromatichydrocarbon group, benzoyl, phenoxy, or phenylthio, or G is a carbonatom, and —Ar is biphenylmethylidene, where said aromatic heterocyclicgroup aromatic hydrocarbon group, benzoyl, phenoxy, phenylthio, andbiphenylmethylidene may optionally be substituted by at least one groupselected from a lower alkyl, a lower alkoxy and a halogen atom}, or anacid addition salt thereof.
 2. The method according to claim 1, wherein—Ar is an aromatic heterobicyclic group, naphthyl, benzoyl, phenoxy orphenylthio, and G is N, CH or COH, or —Ar is biphenylmethylidene, and Gis a carbon atom (said aromatic heterobicyclic group, naphthyl, benzoyl,phenoxy, phenylthio and biphenylmethylidene may optionally besubstituted by at least one group selected from a lower alkyl, a loweralkoxy and a halogen atom).
 3. The method according to claim 1, wherein—Ar is an aromatic heterocyclic group condensed with a benzene ring, ornaphthyl, benzoyl, phenoxy or phenylthio (said aromatic heterocyclicgroup condensed with a benzene ring, naphthyl, benzoyl, phenoxy, andphenylthio may optionally be substituted by at least one group selectedfrom a lower alkyl, a lower alkoxy and a halogen atom), and G is N, CHor COH.
 4. The method according to claim 1, wherein Z is a group of theformula:

in which -L- is a single bond or a double bond, E is a lower alkyleneoptionally substituted by a lower alkyl, or an oxygen atom, R⁵ is ahydrogen atom or a lower alkyl, and B is the same as defined in claim 1;a group of the formula:

in which -L-, E, R⁵ and B are as defined above; a group of the formula:

in which R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ are independentlya hydrogen atom or a lower alkyl, or the adjacent two groups of R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ may combine each other to form adouble bond, and B is as defined above; a group of the formula:

in which R¹⁶ and R¹⁷ are independently a hydrogen atom or a lower alkyl,or R¹⁶ and R¹⁷ may combine each other to form a saturated hydrocarbonring, and R⁵ and B are as defined above; or a group of the formula:

in which B is as defined above.
 5. The method according to claim 1,wherein the senile dementia is selected from the group consisting ofAlzheimer type dementia, cerebrovascular dementia, dementia with Lewybodies, dementia from Pick's disease, dementia from Creutzfeldt-Jakobdisease, dementia from Huntington's chorea and dementia from Parkinson'sdisease.
 6. The method according to claim 1, wherein the senile dementiais Alzheimer type dementia.
 7. The method according to claim 1, whereinthe senile dementia is selected from the group consisting ofcerebrovascular dementia and dementia with Lewy bodies.
 8. A method fortreatment of senile dementia, which comprises administering an effectiveamount of an imide compound of the formula:

or an acid addition salt thereof, and wherein the senile dementia isselected from the group consisting of cerebrovascular dementia, dementiawith Lewy bodies, dementia from Pick's disease, dementia fromCreutzfeldt-Jakob disease and dementia from Huntington's chorea.
 9. Themethod according to claim 8, wherein the senile dementia is selectedfrom the group consisting of cerebrovascular dementia and dementia withLewy bodies.
 10. The method according to claim 8, wherein the seniledementia is cerebrovascular dementia.
 11. The method according to claim8, wherein the senile dementia is dementia with Lewy bodies.